ABSTRACT Historically, platinum-based chemotherapy was the standard of care for metastatic lung cancer. However, since the success of immune checkpoint inhibitors (ICIs) in melanoma, PD-1/PD-L1 and CTLA-4 immune checkpoint pathways have been established as effective therapies to manage advanced non–small cell lung cancer (NSCLC) and extensive-stage (ES) small cell lung cancer (SCLC). Multiple large-scale randomized clinical trials have analyzed the effects of ICIs in NSCLC, and results of these trials have since translated to the approval of single-agent PD-1/PD-L1 inhibitors, and the combination of PD-1 inhibitors with platinum-based chemotherapy has become the new standard of care for patients with advanced NSCLC. Furthermore, in ES SCLC, in which chemotherapy or chemoradiation has been the standard of care for decades, 2 anti–PD-1/PD-L1 agents have been approved for use in the frontline setting for ES SCLC, in combination with chemotherapy. Despite progressive integration of immunotherapy into treatment regimens, there remains a need for reliable biomarkers to precisely determine therapy candidates.
Tumor cells can usurp immune checkpoint signals—CD28/B7 activating signal and CTLA-4 and PD-1/PD-L1 inhibitory signals—to dampen effector T-cell responses to promote tumor cell survival and cancer progression.1 The T-cell costimulation model proposes that T cells require 2 signals in order to be fully activated.2 The first signal provides specificity to the immune reaction through class I major histocompatibility complex (MHC I) and T-cell receptor binding. The second signal is an antigen-independent costimulatory signal to promote T-cell clonal expansion and adequate immune response.Altered interactions between antigen-presenting cells (APC) and T cells can stifle the second costimulatory signal, hinder T-cell activation, and prevent adequate immune response.3 Cancer cells are able to exploit these pathways to evade the immune system and proliferate.3 By introducing immune checkpoint inhibitors (ICI) to target disrupted checkpoint signaling, APC and T-cell interactions can be restored to elicit a lasting antitumor immune response.
PD-1 and PD-L1/PD-L2 Targeted Therapies
The primary function of cytotoxic T cells is to recognize MHC I to induce apoptosis in virus-infected and malignant cells.4 PD-1 is a transmembrane inhibitory receptor that can be found on T cells, B cells, activated monocytes, and dendritic cells.3 It has 2 ligands, PD-L1 and PD-L2. PD-L1 is commonly overexpressed in tumor cells and APC, and PD-L2 is primarily expressed on macrophages and dendritic cells. The binding of PD-L1 and PD-L2 to PD-1 on cytotoxic T cells suppresses the immune system. Therefore, the overexpression of PD-L1 enables cancer cells to impede cytotoxic T-cell function, bypass host antitumor immune response, and proliferate. The goal of anti–PD-1/PD-L1 ICI is to reinstate downregulated T cells and resume normal immune response.
CTLA-4 Targeted Therapies
CTLA-4 is an inhibitory surface receptor expressed on activated dendritic cells and cytotoxic and helper T cells.5 Under normal circumstances, B7 ligands expressed on APCs bind to CD28 surface proteins found on T cells to initiate an immune response against “non-self” cells and avoid autoimmune attack. However, CTLA-4, which has a 10-fold higher affinity for B7, competes with CD28 for B7 binding to curtail CD28/B7 interactions.6 The reduced CD28/B7 activating signal decreases T-cell stimulation and interleukin-2 secretion to repress immune response.7 Competition for B7 binding between CTLA-4 and CD28 downregulates T-cell activation, allowing tumor cells to circumvent detection. Antibodies that target CTLA-4 can interrupt CTLA/B7 binding to restore baseline CD28/B7 interactions and antitumor activity.
First-Line Single Agent Inhibition
Pembrolizumab, an immunoglobulin (Ig) G4 monoclonal anti–PD-1 agent, has shown survival benefit in the frontline setting for patients with metastatic NSCLC as a single-agent monotherapy and with platinum-based agents in combination therapy. KEYNOTE-001, a large phase 1 study, assessed the safety and efficacy of pembrolizumab in locally advanced carcinoma and melanoma, with multiple cohorts of NSCLC patients.8 This was the first study to evaluate the association of PD-L1 levels with patient outcomes in ICI-treated patients. PD-L1 expression was quantified based on immunohistochemical (IHC) assay results, which reported the percentage of cells with PD-L1 in patient tumor samples, known as tumor proportion score (TPS). KEYNOTE-001 trial results exhibited a positive correlation between PD-L1 expression and patient outcomes and differences in treatment response based on the line of therapy.8 In the cohort of treatment-naïve NSCLC patients, the median overall survival (OS), progression-free survival (PFS), and response rate (RR) were 22.3 months, 6.0 months, and 24.8%, respectively. When analyzing RR by smoking status, smokers were more responsive to therapy than nonsmokers (current/former smokers, 22.5%, vs nonsmokers, 10.3%). The 5-year follow-up revealed that patients who received 2 or more years of pembrolizumab (n = 60) with a TPS ≥50% had an estimated 5-year survival of greater than 25%.9 The median OS for patients with TPS ≥50% was 34.5 months; for patients with TPS 1%-49%, it was 19.5 months. KEYNOTE-001 largely illustrates the potential for long-term OS benefits and antitumor responses with pembrolizumab in treatment-naïve and previously treated advanced NSCLC patients. Furthermore, the IHC assay and study results introduced the possibility of outcome advantages owing to high PD-L1 tumor expression.
KEYNOTE-024, an open-label, randomized phase 3 study, compared the effects of pembrolizumab versus platinum-based chemotherapy in treatment-naïve advanced NSCLC patients with PD-L1 expression ≥50% (Table 1).10 At the 3-year follow-up, patients on pembrolizumab had significantly longer median OS (30.0 vs 14.2 months for the chemotherapy arm) despite sizeable crossover from the chemotherapy arm.11 KEYNOTE-024 reported higher estimated 3-year OS rates (43.7% vs 24.9%, respectively) and longer treatment duration (11.1 vs 4.4 months) in addition to having fewer treatment-related adverse events (AEs) in the pembrolizumab arm. The findings suggest that patients with advanced NSCLC and PD-L1 TPS ≥50% can receive significantly greater benefit and longer responses with single-agent immunotherapy over chemotherapy as frontline treatment.
Previous trial results indicate that first-line pembrolizumab monotherapy improves OS and PFS in patients with PD-L1 TPS ≥50%. KEYNOTE-042, a phase 3, randomized trial, investigated OS of first-line, single-agent pembrolizumab monotherapy versus traditional platinum-based chemotherapy for patients with locally advanced or metastatic NSCLC and PD-L1 TPS ≥1% (Table 1).12 Trial results found that all TPS populations reached their primary end point. There was improved median OS in the experimental arm: pembrolizumab, 20.0 months (PD-L1 TPS ≥50%), 17.7 months (PD-L1 TPS ≥20%), and 16.7 months (PD-L1 TPS ≥1%) vs chemotherapy: 10.8 months (PD-L1 TPS ≥50%), 8.3 months (PD-L1 TPS ≥20%), and 8.3 months (PD-L1 TPS ≥1%). When evaluating PFS, only patients with TPS ≥50% in the pembrolizumab arm showed benefit over chemotherapy. Patients with higher PD-L1 expression experienced higher RR regardless of therapy. Duration of response (DOR) with pembrolizumab was consistent across all PD-L1 cohorts (PD-L1 TPS ≥1%, ≥20%, and ≥50%) and superior over chemotherapy. However, upon conducting further survival analysis, pembrolizumab failed to show benefit for patients with TPS 1%-49%. This finding questions the impact of pembrolizumab monotherapy in patients with PD-L1 TPS <50%. The data from KEYNOTE-042 are consistent with those of previous trials and support pembrolizumab monotherapy for patients with PD-L1 expression ≥50%, with survival results from TPS populations ≥1% or ≥20% largely driven by patients with PD-L1 expression ≥50%.
IMpower110, a randomized phase 3 trial, evaluated the effects of atezolizumab with platinum-based chemotherapy.13 This study used the Ventana SP142 IHC assay to quantify PD-L1 expression both in immune cells (IC) and tumor cells (TC). The study found that atezolizumab monotherapy significantly improved OS for TC3 (TC cells with PD-L1 ≥50%) or IC3 (IC cells with PD-L1 ≥10%) over chemotherapy (median OS, 20.2 vs 13.1 months, respectively) in the frontline setting.13,14 The FDA approved atezolizumab monotherapy for first-line treatment of NSCLC for patients with high PD-L1 expression in May 2020, based on IMpower110 trial results.15
Nivolumab, an anti–PD-1 ICI, has also been studied in the frontline setting. CheckMate 026, a randomized phase 3 trial, evaluated frontline nivolumab vs chemotherapy in patients with stage IV or recurrent advanced NSCLC with PD-L1 expression ≥5%. Nivolumab was not found to be superior over chemotherapy in PFS and RR, nor did it significantly increase OS (PFS, 4.2 vs 5.9 months, respectively; RR, 26% vs 33%; OS, 14.4 vs 13.2 months) (Table 1).16 However, despite unremarkable PFS and RR, the DOR for patients treated with nivolumab was more than twice as long as for those in the chemotherapy arm (12.1 vs 5.7 months, respectively).
The trial acknowledged several imbalances between patient characteristics: The percentage of patients with disease characteristics associated with better prognosis, PD-L1 expression ≥50% and high tumor mutational burden (TMB), may have disadvantaged the nivolumab arm and favored chemotherapy. TMB subset analysis was motivated by findings from Rizvi and colleagues, who used whole exome sequencing to determine TMB and reported an association between high TMB and improved immunotherapy treatment response.17 In CheckMate 026, the analysis indicated that patients with high TMB (≥243 somatic missense mutations) in the nivolumab arm had increased RR and longer PFS than patients on chemotherapy (RR, 47% vs 28%, respectively; PFS, 9.7 vs 5.8 months.16 Moreover, high-TMB patients treated with nivolumab also experienced notable benefit in OS and 1-year survival rates ( >18 months and 64%, respectively). These TMB subset analysis data agree with the proposed hypothesis that immunotherapy responses may be augmented in patients with high TMB.
Combination Anti–PD-1/PD-L1 and Chemotherapy
Various immunotherapy + chemotherapy combination trials have demonstrated encouraging results for patients with advanced NSCLC. KEYNOTE-189 and KEYNOTE-407 assessed the effects of pembrolizumab in combination with chemotherapy vs chemotherapy alone in untreated metastatic nonsquamous (KEYNOTE-189) and squamous NSCLC (KEYNOTE-407) (Table 1).18,19 In KEYNOTE-189, RR, PFS, and OS were significantly superior in the pembrolizumab/chemotherapy arm vs the placebo/ chemotherapy arm, with benefit in OS seen across all TPS subgroups (OS, 22.0 vs 10.7 months, respectively; PFS, 9.0 vs 4.9 months; RR, 47.6% vs 18.9%).18 The 2-year follow-up concluded that the pembrolizumab/chemotherapy patient arm continued to display OS benefit in 2-year OS rate (46% vs 30% for placebo/chemotherapy) despite 54% of placebo/chemotherapy patients crossing over to anti–PD-1/PD-L1 therapy.20 In KEYNOTE-407, patients who received pembrolizumab/chemotherapy experienced greater survival benefit than those who received placebo/chemotherapy (OS, 15.9 vs 11.3 months, respectively; PFS, 6.4 vs 4.8 months; RR, 57.9% vs 38.4%).19 In both studies, subgroup statistical analysis of varying PD-L1 expression (TPS ≤1%, TPS ≥1%, TPS ≥50%) pointed toward pembrolizumab combination therapy as the superior treatment regardless of PD-L1 status. Clinical trials KEYNOTE-189 and KEYNOTE-407 support the role of pembrolizumab in the first-line setting for metastatic NSCLC regardless of histology or PD-L1 expression, contrary to the findings of previous trials.18,19
IMpower130, a randomized phase 3 trial, evaluated the effects of carboplatin and nab-paclitaxel (CnP) with or without atezolizumab in advanced nonsquamous NSCLC.21 Atezolizumab provided significant improvement in median OS and PFS across all PD-L1 subgroups and prognostic subgroups except in patients with liver metastases and those harboring EGFR or ALK mutations (OS, 18.6 vs 13.9 months, respectively; PFS, 7.0 vs 5.5 months). The ORR and percentage of grade 3/4 AEs were higher for the atezolizumab + CnP arm (ORR, 49.2% vs 31.9%, respectively; grade 3/4 AEs, 72.3% vs 60.3%).
IMpower150, a randomized, phase 3 clinical trial, investigated immunotherapy plus chemotherapy and bevacizumab in the frontline setting for patients with advanced NSCLC (Table 1).22 Patients with advanced nonsquamous NSCLC were randomized to 1 of 3 arms: atezolizumab (a human IgG1 monoclonal antibody to PD-L1) with carboplatin plus paclitaxel; atezolizumab and bevacizumab with carboplatin plus paclitaxel (ABCP); or placebo with bevacizumab and chemotherapy (BCP). Typically, studies exclude patients with EGFR- and ALK-activating alterations; however, IMpower150 enrolled patients harboring EGFR- and ALK-activating mutations following first-line tyrosine kinase therapy. The RR for the ABCP arm was 63.5%, exceeding the BCP treatment group’s RR of 48.0%. A significant OS benefit, as well as improvement in PFS regardless of PD-L1 expression, presence of liver metastases, and sensitization for EGFR or ALK mutations, was observed in the ABCP vs the BCP treatment arm (OS, 19.2 vs 14.7 months, respectively; PFS, 8.3 vs 6.8 months). Historically, trials of second-line or greater treatment have shown that patients with EGFR genetics do not benefit from checkpoint inhibition.23-25 IMpower150 was a pivotal study in that it was first trial to report a benefit from ICI therapy for patients with EGFR- and ALK-altered NSCLC.
Combination CTLA-4 and Chemotherapy
Ipilimumab is an anti–CTLA-4 monoclonal antibody that first showed survival benefit in melanoma.26 A phase 2 clinical trial compared the effects of paclitaxel and carboplatin with placebo or ipilimumab as first-line therapy for patients with advanced NSCLC.27 Patients were randomly assigned 1:1:1 to each treatment arm and received concurrent dosing (4 doses of 10 mg/kg ipilimumab with paclitaxel and carboplatin followed by 2 doses of paclitaxel and carboplatin), phased dosing (2 doses of paclitaxel and carboplatin followed by 4 doses of ipilimumab in combination with paclitaxel and carboplatin), or control (up to 6 cycles of paclitaxel and carboplatin). Immune-related PFS was improved with phased therapy over placebo (5.7 vs 4.6 months, respectively). When comparing OS and RR among phased dosing, concurrent dosing, and chemotherapy, both phased and concurrent dosing reached statistically insignificant numerical outcomes favorable over control (OS, 12.2 vs 9.7 vs 8.3 months, respectively; RR, 32%, 21%, and 14%). Furthermore, the addition of ipilimumab produced an increase in grade 3/4 AEs (6%, 20%, and 15% for control, concurrent, and phased arms, respectively). Despite unremarkable findings of ipilimumab + chemotherapy combination treatment in NSCLC compared with PD-1/PD-L1 ICIs, ongoing ipilimumab trials have since focused attention on the benefit of ipilimumab in combination with nivolumab and other immune-modulating therapies.
The advantages of anti–PD-1/PD-L1 monotherapy, and of anti–PD-1/PD-L1 + chemotherapy, over traditional platinum-based therapy have inspired trials to study the effects of anti–PD-1/PD-L1 agents in combination with anti–CTLA-4 agents. By combining therapies of 2 independent pathways, the treatments can hopefully complement each other therapeutically to enhance RR and survival outcomes.28
CheckMate 227, a phase 3 randomized study, evaluated the effects of nivolumab plus ipilimumab in patients with advanced NSCLC as first-line therapy. Patients with PD-L1 ≥1% were randomly assigned to receive nivolumab + ipilimumab, nivolumab monotherapy, or chemotherapy.29 Patients with PD-L1 <1% were randomly assigned to nivolumab + ipilimumab, nivolumab + chemotherapy, or chemotherapy, and did not have a statistical end point included. PD-L1 expression and TMB were used to assess outcomes in patient subgroups (Table 1).30 Contrary to the results of previous immunotherapy trials,9-11 CheckMate 227 reported higher median OS and 2-year ongoing RR in patients who received ipilimumab + nivolumab than in patients treated with chemotherapy alone, regardless of PD-L1 expression (median OS, 17.1 vs 14.9 months, respectively; 2-year rate of ongoing response: 49% vs 11%).28 Median PFS was also improved with nivolumab + ipilimumab over chemotherapy for all patients regardless of PD-L1 expression, but it was numerically higher for patients with PD-L1 expression <1%. Initial reports also indicated that patients with high TMB (TMB ≥10 mut/MB) across PD-L1 ≥1% and <1% subgroups saw improved PFS when treated with nivolumab + ipilimumab over chemotherapy.29 Researchers expected to see an association between TMB and treatment response based on the results from CheckMate 568.31 However, upon performing a further subset analysis based on TMB, the data revealed consistent median OS regardless of TMB. These findings prompted the approval of nivolumab + ipilimumab as a first-line treatment for advanced NSCLC patients with PD-L1 expression ≥1%.31 CheckMate 227 highlights the reality that ICI and TMB biomarkers used to predict patient response remain elusive and warrant further investigation and validation.
Building off CheckMate 227, CheckMate 9LA, a randomized phase 3 trial, compared nivolumab + ipilimumab + 2 cycles of chemotherapy vs 4 cycles of chemotherapy alone.32 At the 12.7-month follow-up, regardless of PD-L1 expression, patients treated with nivolumab and ipilimumab with limited-course chemotherapy saw significantly improved median OS (15.6 vs 10.9 months, respectively) and higher percentage of patients with grade 3/4 AEs (47% vs 38%, respectively).
KEYNOTE-001 evaluated pembrolizumab in both treatment-naïve and previously treated patients.8 Previously treated patients had an 18% RR compared with the observed 45.2% RR for patients with PD-L1 TPS ≥50%. At the 5-year follow up, previously treated patients with TPS ≥50% had a median OS of 15.4 months versus 8.5 months for those with TPS 1%-49% and 8.6 months for those with TPS <1% (estimated 5-year survival rates were 25% vs 12.6% vs 3.5%, respectively).9
KEYNOTE-010 also compared pembrolizumab (2 mg/kg or 10 mg/kg) with docetaxel for previously treated NSCLC patients with PD-L1 TPS ≥1%.25 There was no significant difference in overall PFS across treatments, but when taking TPS into account, PFS was significantly higher in patients who were administered pembrolizumab vs docetaxel. The median OS of patients with TPS ≥1% was 10.4 months with 2 mg/kg pembrolizumab, 12.7 months with 10 mg/kg pembrolizumab, and 8.4 months with docetaxel. For patients with TPS ≥50%, the median OS was significantly higher with 2 mg/kg and 10 mg/kg doses of pembrolizumab: 14.9 and 17.3 months, respectively. The long-term outcomes of KEYNOTE-001 and KEYNOTE-010illuminate the success of pembrolizumab monotherapy in the frontline setting and the association of high PD-L1 expression with favorable treatment response.
CheckMate 017 and CheckMate 057, both randomized phase 3 trials, evaluated the effects of nivolumab vs docetaxel in patients with advanced squamous (CheckMate 017) and nonsquamous (CheckMate 057) NSCLC (Table 2).24,33,34 The results of CheckMate 017 indicated a 20% RR with nivolumab vs a 9% RR with docetaxel, and significantly longer PFS and OS with nivolumab over docetaxel (PFS, 3.5 vs 2.8 months, respectively; OS, 9.2 vs 6.0 months).33 From the results, no predictive association could be concluded upon evaluating PD-L1 expression with treatment efficacy. In CheckMate 057, patients on nivolumab experienced significantly improved OS versus those on docetaxel (12.2 vs 9.4 months, respectively), improved RR (19% vs 12%), and shorter PFS (2.3 vs 4.2 months).24 Contrary to CheckMate 017, CheckMate 057 identified a correlation between high PD-L1 expression and improved response. At the 5-year follow-up for CheckMate 017/CheckMate 057, nivolumab continued to show long-term OS and PFS benefit over docetaxel for both squamous and nonsquamous NSCLC, with 5-year OS rates of 15% vs 3% and 5-year PFS rates of 8% vs 0%, respectively.34
OAK, a randomized phase 3 study, compared atezolizumab to docetaxel in previously treated, advanced NSCLC. Atezolizumab displayed a better safety and survival profile vs docetaxel in the intention-to-treat group regardless of PD-L1 expression (OS, 13.8 vs 9.6 months, respectively) or histology.23 When quantifying for PD-L1 expression, median OS and PFS improved in higher PD-L1 expression groups. At the 7-month follow-up, the results were consistent, as atezolizumab continued to show improved survival benefit over docetaxel in the secondary intention-to-treat population (OS, 13.3 vs 9.8 months, respectively).35 OAK was the first study to indicate improved survival benefits with atezolizumab in NSCLC.
Durvalumab is a PD-L1 inhibitor that acts to disrupt PD-L1 binding to PD-1 and CD80. This differs from pembrolizumab and nivolumab, because binding to PD-L1 inhibits PD-1/PD-L1 binding while anti–PD-1 therapy interrupts PD-1/PD-L1 and PD-1/PD-L2 interactions.36 The PACIFIC trial evaluated consolidation durvalumab and placebo for 12 months following concurrent chemoradiation for patients with unresectable stage III NSCLC (Table 3).Significant improvement in 12- and 24-month OS rate, PFS, and RR was seen for patients on durvalumab vs those on placebo (12-month OS rate: 83.1% vs 75.3%, respectively; 24-month OS rate: 66.3% vs 55.6%; PFS, 17.2 vs 5.6 months; RR, 28.4% vs 16.0%), regardless of PD-L1 expression.36,37 At the 3-year follow-up, median OS in the placebo arm was 29.1 months while median OS was still unreached in the durvalumab arm.38 Findings from the PACIFIC trial and the 3-year follow-up reinforces the use of consolidation durvalumab as the standard of care for unresectable stage III NSCLC. In earlier-stage NSCLC, in which surgery is the standard of care and OS remains below 50%, ongoing trials continue to address the integration of perioperative immunotherapy to improve survival and quality of life for more patients with lung cancer.
First-line treatment for patients with extensive stage small cell lung cancer (ES SCLC) is platinum-based chemotherapy with or without radiation; this has been the standard of care for more than 3 decades.39 Although SCLC patients initially respond to chemotherapy, relapse is common and the number of available second-line treatments is limited. Given the effectiveness of immunotherapy in NSCLC and high TMB SCLC, ongoing trials are exploring how immune-based modalities can be incorporated into new treatment regimens for ES SCLC.
IMpower133, a randomized phase 3 trial, compared carboplatin and etoposide with or without atezolizumab in patients with untreated ES SCLC (Table 4).40 IMpower133 was the first trial to demonstrate significant improvement in median OS and PFS with an immunotherapy-based regimen. The median OS and PFS for patients with atezolizumab were 12.3 and 5.2 months, respectively, versus 10.3 and 4.3 months for placebo (survival results and were consistent across TMB subgroups).
CASPIAN, a large, randomized, open-label phase 3 trial, evaluated platinum + etoposide with or without durvalumab as a first-line treatment for ES SCLC.39 Durvalumab plus platinum/etoposide was associated with manageable immune-related AEs, improved median OS with durvalumab over no durvalumab (13.0 vs 10.3 months, respectively), and an improved median 18-month OS rate (34% vs 25%). Similar to the IMpower133 results, survival results were consistent across TMB subgroups. The strong and promising efficacy and safety data gathered from the IMpower133 and CASPIAN trials have resulted in FDA approval of atezolizumab and durvalumab as optional additions to the standard of care when treating ES SCLC. These approvals mark the first amendments to the standard of care for first-line ES SCLC treatment in decades.
KEYNOTE-604, a randomized phase 3 trial, evaluated pembrolizumab + platinum + etoposide versus placebo + platinum + etoposide in patients with untreated ES SCLC.41 Pembrolizumab + platinum + etoposide significantly improved 12-month PFS estimates (13.6% vs 3.1% for placebo) and showed no unexpected toxicities. Although median OS with pembrolizumab did not reach statistically significant improvement over placebo (10.8 vs 9.7 months, respectively), the study results support the benefit and safety of pembrolizumab + platinum + etoposide for untreated ES SCLC.
Despite the progress that has been made with immunotherapy for lung cancer patients, the vast majority of patients do not respond to ICI. Accurate and consistent biomarkers and assays are critical to improve patient sensitivity to ICI treatment. Previous clinical trials have demonstrated some association between PD-L1 and TMB and treatment response. However, both measures are elusive and have shown inconsistencies across trials in their ability to predict treatment response.8-10,18,19,28,30
Multiple antibody-staining PD-L1 IHC assays have been approved as companion diagnostics for ICIs, and high TMB was approved in June 2020 as a diagnostic for pembrolizumab across tumor types.42 The FDA has approved the PD-L1 IHC 22C3 and 28-8 assays; these use 223C and 28-8 antibodies, respectively, to stain patient tumor samples and determine the percentage of cells with membranous PD-L1.43 The percentage of stained cells is the patient’s TPS for the IHC 22C3 assay, which is used to identify individuals eligible for pembrolizumab.44 The PD-L1 IHC 28-8 assay quantifies PD-L1 expression to identify patients who are suitable for second-line nivolumab for nonsquamous NSCLC and first-line nivolumab plus ipilimumab in NSCLC patients.45 Meanwhile, the Ventana SP142 IHC assay quantifies PD-L1 expression of IC and TC. Depending on the percentage of stained IC and TC cells, PD-L1 expression will be scored as TC1, 2, or 3 (TC1: PD-L1 ≥1%; TC2: PD-L1 ≥5%; TC3: PD-L1 ≥50%) and IC1, 2, or 3 (IC1: PD-L1 ≥1%; IC2: PD-L1 ≥5%; IC3: PD-L1 ≥10%). Based on IMpower110 study results, the Ventana SP142 IHC assay has been approved as a companion diagnostic for first-line atezolizumab monotherapy.15
Due to the nature of high tumor heterogeneity in advanced NSCLC and ES SCLC, determining PD-L1 expression and TMB has been challenging. Both tests require adequate tissue biopsies, which may not always be feasible or accessible; moreover, even if tissue is available, test results may not be indicative of the tumor microenvironment due to tumor heterogeneity.46-48 The obstacles faced with tissue biopsies have instigated research and validation to use blood samples and blood TMB (bTMB).49 bTMB is determined through next-generation sequencing (NGS) of circulating-tumor DNA (ctDNA), pieces of DNA shed by the tumor in its surrounding microenvironment. By using NGS on ctDNA, the number of mutations in ctDNA can be calculated to determine bTMB. Analyses performed on POPLAR and OAK blood samples found that bTMB ≥16 mutations/Mb is a clinically meaningful predictor of PFS for NSCLC atezolizumab patients.46 The analysis also observed improved OS with bTMB with the POPLAR study, but the OAK trial was unable to validate those results, which Gandara et al attributed to superior OS benefit in the biomarker-evaluable population relative to the intention-to-treat population.
Although bTMB is a noninvasive test, its success depends on the tumor shedding DNA and on the blood samples to contain ctDNA; if no DNA is shed or found, the blood sample is insufficient and cannot determine bTMB. Furthermore, blood samples must contain a minimum amount of ctDNA and mutations in the ctDNA in order for bTMB results to be considered accurate. Despite the limitations inherent in each method— tTMB, bTMB, and PD-L1 IHC assays—these are the best predictors available until more suitable biomarkers and assays are validated.
Understanding anti–PD-1/PD-L1 and anti-CTLA4 immunomodulators have dramatically altered the treatment approach to lung cancer. In advanced NSCLC, the effective, durable, and manageable toxicity profiles of ICI over chemotherapy have culminated in FDA approvals for multiple agents in all treatment lines and have even become the new standard of care. In ES SCLC, checkpoint inhibitors are being incorporated into therapies, and their inclusion to the standard of care shows promise. As ongoing trials continue to explore the utility of various single-agent and combination therapies, the urgent need for reliable biomarkers remains. Although PD-L1 expression remains the primary FDA approved biomarker, the field is developing TMB as a biomarker to identify patients suitable for immunotherapy. Due to the survival benefit and durable responses immunotherapy provides, studies continue to evaluate novel immune-modulating combinations to resume innate antitumor activity and improve long-term survival for all lung cancer patients.
1. Vinay DS, Ryan EP, Pawelec G, et al. Immune evasion in cancer: Mechanistic basis and therapeutic strategies. Semin Cancer Biol. 2015;35 Suppl:S185-S198. doi:10.1016/j.semcancer.2015.03.004
2. Lafferty KJ, Cunningham AJ. A new analysis of allogeneic interactions. Aust J Exp Biol Med Sci. 1975;53(1):27-42. doi:10.1038/icb.1975.3
3. Seidel JA, Otsuka A, Kabashima K. Anti-PD-1 and anti-CTLA-4 therapies in cancer: mechanisms of action, efficacy, and limitations. Front Oncol. 2018;8:86. doi:10.3389/fonc.2018.00086
4. Keir ME, Butte MJ, Freeman GJ, Sharpe AH. PD-1 and its ligands in tolerance and immunity. Annu Rev Immunol. 2008;26:677-704. doi:10.1146/annurev.immunol.26.021607.090331
5. Pennock ND, White JT, Cross EW, et al. T cell responses: naive to memory and everything in between. Adv Physiol Educ. 2013;37(4):273-283. doi:10.1152/advan.00066.2013
6. van der Merwe PA, Bodian DL, Daenke S, et al. CD80 (B7-1) binds both CD28 and CTLA-4 with a low affinity and very fast kinetics. J Exp Med. 1997;185(3):393-403. doi:10.1084/jem.185.3.393
7. Wu Y, Guo Y, Huang A, et al. CTLA-4-B7 interaction is sufficient to costimulate T cell clonal expansion. J Exp Med. 1997;185(7):1327-1335. doi:10.1084/jem.185.7.1327
8. Garon EB, Rizvi NA, Hui R, et al; KEYNOTE-001 Investigators. Pembrolizumab for the treatment of non-small-cell lung cancer. N Engl J Med. 2015;372(21):2018-2028. doi:10.1056/NEJMoa1501824
9. Garon EB, Hellmann MD, Rizvi NA, et al. Five-year overall survival for patients with advanced non-small-cell lung cancer treated with pembrolizumab: results from the phase I KEYNOTE-001 study. J Clin Oncol. 2019;37(28):2518-2527. doi:10.1200/JCO.19.00934
10. Reck M, Rodríguez-Abreu D, Robinson AG, et al; KEYNOTE-024 Investigators. Pembrolizumab versus chemotherapy for PD-L1–positive non–small-cell lung cancer. N Engl J Med. 2016;375(19):1823-1833. doi:10.1056/NEJMoa1606774
11. Reck M, Rodríguez-Abreu D, Robinson AG, et al. OA14.01 KEYNOTE-024 3-year survival update: pembrolizumab vs platinum-based chemotherapy for advanced non–small-cell lung cancer. J Thorac Oncol. 2019;14(10):S243. doi:10.1016/j.jtho.2019.08.483
12. Mok TSK, Wu Y-L, Kudaba I, et al; KEYNOTE-042 Investigators. Pembrolizumab versus chemotherapy for previously untreated, PD-L1-expressing, locally advanced or metastatic non-small-cell lung cancer (KEYNOTE-042): a randomised, open-label, controlled, phase 3 trial. Lancet. 2019;393(10183):1819-1830. doi:10.1016/S0140-6736(18)32409-7
13. Spigel DE, de Marinis F, Giaccone G, et al. IMPower110: Interim overall survival (OS) analysis of a phase III study of atezolizumab (atezo) vs platinum-based chemotherapy (chemo) as first-line (1L) treatment (TX) in PD-L1- selected NSCLC. Ann Onc. 2019;30(suppl 5):v851-v934. doi:10.1093/annonc/mdz394
14. Vennapusa B, Baker B, Kowanetz M, et al. Development of a PD-L1 complementary diagnostic immunohistochemistry assay (SP142) for atezolizumab. Appl Immunohistochem Mol Morphol. 2019;27(2):92-100. doi:10.1097/PAI.0000000000000594
15. FDA approves atezolizumab for first-line treatment of metastatic NSCLC with high PD-L1 expression. May 18, 2020. Accessed June 27, 2020. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-atezolizumab-first-line-treatment-metastatic-nsclc-high-pd-l1-expression
16. Carbone DP, Reck M, Paz-Ares L, et al; CheckMate 026 Investigators. First-line nivolumab in stage IV or recurrent non–small-cell lung cancer. N Engl J Med. 2017;376(25):2415-2426. doi:10.1056/NEJMoa1613493
17. Rizvi NA, Hellmann MD, Snyder A, et al. Cancer immunology. mutational landscape determines sensitivity to PD-1 blockade in non-small cell lung cancer. Science. 2015;348(6230):124-128. doi:10.1126/science.aaa1348
18. Gandhi L, Rodríguez-Abreu D, Gadgeel S, et al; KEYNOTE-189 Investigators. Pembrolizumab plus chemotherapy in metastatic non–small-cell lung cancer. N Engl J Med. 2018;378(22):2078-2092. doi:10.1056/NEJMoa1801005
19. Paz-Ares L, Luft A, Vicente D, et al; KEYNOTE-407 Investigators. Pembrolizumab plus chemotherapy for squamous non–small-cell lung cancer. N Engl J Med. 2018;379(21):2040-2051. doi:10.1056/NEJMoa1810865
20. Gadgeel S, Rodríguez-Abreu D, Speranza G, et al. Updated analysis from KEYNOTE-189: pembrolizumab or placebo plus pemetrexed and platinum for previously untreated metastatic nonsquamous non–small-cell lung cancer. J Clin Oncol. 2020;38(14)1505-1517. doi:10.1200/JCO.19.03136
21. West HL, McCleod M, Hussein M, et al. IMpower130: progression-free survival (PFS) and safety analysis from a randomized phase 3 study of carboplatin + nab-paclitaxel (CnP) with or without atezolizumab as first-line (1L) therapy in advanced non-squamous NSCLC. Cancer Res. 2019;79(suppl 13; abstr CT200). doi:10.1158/1538-7445.AM2019-CT200
22. Socinski MA, Jotte RM, Cappuzzo F, et al; IMppower150 Study Group. Atezolizumab for first-line treatment of metastatic nonsquamous NSCLC. N Engl J Med. 2018;378(24):2288-2301. doi:10.1056/NEJMoa1716948
23. Rittmeyer A, Barlesi F, Waterkamp D, et al; OAK Study Group. Atezolizumab versus docetaxel in patients with previously treated non-small-cell lung cancer (OAK): a phase 3, open-label, multicentre randomised controlled trial. Lancet. 2017;389(10066):255-265. doi:10.1016/S0140-6736(16)32517-X
24. Borghaei H, Paz-Ares L, Horn L, et al. Nivolumab versus docetaxel in advanced nonsquamous non–small-cell lung cancer. N Engl J Med. 2015;373(17):1627-1639. doi:10.1056/NEJMoa1507643
25. Herbst RS, Baas P, Kim D-W, et al. Pembrolizumab versus docetaxel for previously treated, PD-L1-positive, advanced non-small-cell lung cancer (KEYNOTE-010): a randomised controlled trial. Lancet. 2016;387(10027):1540-1550. doi:10.1016/S0140-6736(15)01281-7
26. Hodi FS, O’Day SJ, McDermott DF, et al. Improved survival with ipilimumab in patients with metastatic melanoma. N Engl J Med. 2010;363(8):711-723. doi:10.1056/NEJMoa1003466
27. Lynch TJ, Bondarenko I, Luft A, et al. Ipilimumab in combination with paclitaxel and carboplatin as first-line treatment in stage IIIB/IV non–small-cell lung cancer: results from a randomized, double-blind, multicenter phase II study. J Clin Oncol. 2012;30(17):2046-2054. doi:10.1200/JCO.2011.38.4032
28. Hellmann MD, Paz-Ares L, Bernabe Caro R, et al. Nivolumab plus ipilimumab in advanced non–small-cell lung cancer. N Engl J Med. 2019;381(21):2020-2031. doi:10.1056/NEJMoa1910231
29. Hellmann MD, Ciuleanu T-E, Pluzanski A, et al. Nivolumab plus ipilimumab in lung cancer with a high tumor mutational burden. N Engl J Med. 2018;378(22):2093-2104. doi:10.1056/NEJMoa1801946
30. Ready N, Hellmann MD, Awad MM, et al. First-line nivolumab plus ipilimumab in advanced non–small-cell lung cancer (CheckMate 568): outcomes by programmed death ligand 1 and tumor mutational burden as biomarkers. J Clin Oncol. 2019;37(12):992-1000. doi:10.1200/JCO.18.01042
31. FDA approves nivolumab plus ipilimumab for first-line mNSCLC (PD-L1 tumor expression ≥1%). May 15, 2020. Accessed June 27, 2020. https://www.fda.gov/drugs/drug-approvals-and-databases/fda-approves-nivolumab-plus-ipilimumab-first-line-mnsclc-pd-l1-tumor-expression-1
32. Reck M, Ciuleanu T-E, Dols MC, et al. Nivolumab (NIVO) + ipilimumab (IPI) + 2 cycles of platinum-doublet chemotherapy (chemo) vs 4 cycles chemo as first-line (1L) treatment (tx) for stage IV/recurrent non-small cell lung cancer (NSCLC): CheckMate 9LA. J Clin Oncol. 2020;38(15 suppl; abstr 9501). doi:10.1200/JCO.2020.38.15_suppl.9501
33. Brahmer J, Reckamp KL, Baas P, et al. Nivolumab versus docetaxel in advanced squamous-cell non–small-cell lung cancer. N Engl J Med. 2015;373(2):123-135. doi: 10.1056/NEJMoa1504627
34. Gettinger S, Borghaei H, Brahmer JR, et al. OA14.04 Five-year outcomes from the randomized, phase 3 trials CheckMate 017/057: nivolumab vs docetaxel in previously treated NSCLC. J Thorac Oncol. 2019;14(10):S244-S245. doi:10.1016/j.jtho.2019.08.486
35. Fehrenbacher L, von Pawel J, Park K, et al. Updated efficacy analysis including secondary population results for OAK: a randomized phase III study of atezolizumab versus docetaxel in patients with previously treated advanced non–small cell lung cancer. J Thorac Oncol. 2018;13(8):1156-1170. doi:10.1016/j.jtho.2018.04.039
36. Antonia SJ, Villegas A, Daniel D, et al; PACIFIC Investigators. Durvalumab after chemoradiotherapy in stage III non–small-cell lung cancer. N Engl J Med. 2017;377(20):1919-1929. doi:10.1056/NEJMoa1709937
37. Antonia SJ, Villegas A, Daniel D, et al; PACIFIC Investigators. Overall survival with durvalumab after chemoradiotherapy in stage III NSCLC. N Engl J Med. 2018;379(24):2342-2350. doi:10.1056/NEJMoa1809697
38. Gray JE, Villegas AE, Daniel DB, et al. Three-year overall survival update from the PACIFIC trial. J Clin Oncol. 2019;37(15 suppl; abstr 8526). doi:10.1200/JCO.2019.37.15_suppl.8526
39. Paz-Ares L, Dvorkin M, Chen Y, et al; CASPIAN Investigators. Durvalumab plus platinum–etoposide versus platinum–etoposide in first-line treatment of extensive-stage small-cell lung cancer (CASPIAN): a randomised, controlled, open-label, phase 3 trial. Lancet. 2019;394(10212):1929-1939. doi:10.1016/S0140-6736(19)32222-6
40. Horn L, Mansfield AS, Szczęsna A, et al; IMpower133 Study Group. First-line atezolizumab plus chemotherapy in extensive-stage small-cell lung cancer. N Engl J Med. 2018;379(23):2220-2229. doi:10.1056/NEJMoa1809064
41. Rudin CM, Awad MM, Navarro A, et al; KEYNOTE-604 Investigators. Pembrolizumab or placebo plus etoposide and platinum as first-line therapy for extensive-stage small-cell lung cancer: randomized, double-blind, phase III KEYNOTE-604 study. J Clin Oncol. Published online May 29, 2020. doi:10.1200/JCO.20.00793
42. FDA approves pembrolizumab for adults and children with TMB-H solid tumors. FDA. June 17, 2020. Accessed June 22, 2020. https://www.fda.gov/drugs/drug-approvals-and-databases/fda-approves-pembrolizumab-adults-and-children-tmb-h-solid-tumors
43. Roach C, Zhang N, Corigliano E, et al. Development of a companion diagnostic PD-L1 immunohistochemistry assay for pembrolizumab therapy in non-small-cell lung cancer. Appl Immunohistochem Mol Morphol. 2016;24(6):392-397. doi:10.1097/PAI.0000000000000408
44. PD-L1 IHC 22C3 pharmDx overview. Agilent. Accessed June 27, 2020. https://www.agilent.com/en-us/pd-l1-ihc-22c3-pharmdx-overview
45. PD-L1 IHC 28-8 pharmDx overview. Agilent. Accessed June 27, 2020. https://www.agilent.com/en-us/product/pharmdx/pd-l1-ihc-28-8-overview
46. Gandara DR, Paul SM, Kowanetz M, et al. Blood-based tumor mutational burden as a predictor of clinical benefit in non-small-cell lung cancer patients treated with atezolizumab. Nat Med. 2018;24(9):1441-1448. doi:10.1038/s41591-018-0134-3
47. Jamal-Hanjani M, Wilson GA, McGranahan N, et al; TRACERx Consortium. Tracking the evolution of non–small-cell lung cancer. N Engl J Med. 2017;376(22):2109-2121. doi:10.1056/NEJMoa1616288
48. Lim C, Tsao MS, Le LW, et al. Biomarker testing and time to treatment decision in patients with advanced nonsmall-cell lung cancer. Ann Oncol. 2015;26(7):1415-1421. doi:10.1093/annonc/mdv208
49. Siravegna G, Marsoni S, Siena S, Bardelli A. Integrating liquid biopsies into the management of cancer. Nat Rev Clin Oncol. 2017;14(9):531-548. doi:10.1038/nrclinonc.2017.14
50. Herbst RS, Garon EB, Kim D, et al. Long-term outcomes and retreatment among patients with previously treated, programmed death-ligand 1‒positive, advanced non‒small-cell lung cancer in the KEYNOTE-010 study. J Clin Oncol. 2020;38(14):1580-1590. doi:10.1200/JCO.19.02446stylefix